Heteroaryl substituted 2-pyridinyl and 2-pyrimidinyl -6,7,8,9-tetrahydropyrimido[1,2-a] pyrimidin-4-one derivatives

ABSTRACT

The invention relates to use of a pyrimidone derivative represented by formula (I)or a salt thereof wherein: 
                         
X, Y, R1, R2, R3, R4, R5, m, n and p are as defined herein. In particular, the invention relates to a medicament comprising the said derivative or a salt thereof as an active ingredient which is used for preventive and/or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3β or GSK3β and cdk5/p25, such as Alzheimer disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/504,677, filed Mar. 24, 2005, now U. S. Pat. No. 7,232,827 B1,issued, Jun. 19, 2007, which was the National Stage of Internationalapplication No. PCT/EPO3/02,651, filed Feb. 26, 2003; both of which areincorporated herein by reference in their entirety; which claims thebenefit of priority of European Patent Application No. 02290485.8, filedFeb. 28

TECHNICAL FIELD

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof neurodegenerative diseases caused by abnormal activities of GSK3βalone or by the combined effects of GSK3β and cdk5/p25.

BACKGROUND ART

GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral taupathies.

Interestingly, protein kinase B (AKT) phosphorylation of GSK3β resultsin a loss of its kinase activity, and it has been hypothesized that thisinhibition may mediate some of the effects of neurotrophic factors.Moreover, phosphorylation by GSK3β of β-catenin, a protein involved incell survival, results in its degradation by an ubiquitinilationdependent proteasome pathway.

Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anon-competitive inhibitor of GSK3β, enhances neuritogenesis in somemodels and also increases neuronal survival, through the induction ofsurvival factors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as P53 and Bax.

Recent studies have demonstrated that β-amyloid increases the GSK3βactivity and tau protein phosphorylation. Moreover, thishyperphosphorylation as well as the neurotoxic effects of β-amyloid areblocked by lithium chloride and by a GSK3β antisense mRNA. Theseobservations strongly suggest that GSK3β may be the link between the twomajor pathological processes in Alzheimer's disease: abnormal APP(Amyloid Precursor Protein) processing and tau proteinhyperphosphorylation.

Although tau hyperphosphorylation results in a destabilization of theneuronal cytoskeleton, the pathological consequences of abnormal GSK3βactivity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors. Moreover, it hasbeen shown that β-amyloid-induced increase in GSK3β activity results inthe phosphorylation and, hence the inhibition of pyruvate dehydrogenase,a pivotal enzyme in energy production and acetylcholine synthesis.

Cdk5/p25, also known as tau protein kinase 2 (TPK2), is a prolinedirected, Ser/Thr kinase essential for central nervous systemdevelopment and in particular for neuronal migration and neuriteoutgrowth. Cdk5 is a homologue of cyclin-dependent kinases and ratherubiquitously expressed. Its activator p35 (a 305 aa protein) or atruncated form p25 (208 aa, missing an N-terminal proline-rich domainnot required for activity) are selectively expressed in neurons,limiting cdk5 kinase activity essentially to the CNS. Cdk5 is completelyinactive in the absence of p35 or p25. The term cdk5/p25 will be usedhere for the active enzyme since evidence exists suggesting that p25 andless so p35 may be involved in pathological processes.

Physiological substrates of cdk5/p25 include DARPP-32, Munc-18, PAK1,synapsin 1 and perhaps some others. In addition, it is now wellestablished that cdk5/p25 phosphorylates tau protein epitopes which arehyperphosphorylated in Alzheimer's disease. More recently, elevatedcdk5/p25 activity, mislocalization of cdk5 and an increase in p25activator has been found in the brain of Alzheimer patients.Interestingly, prephosphorylation of tau protein by cdk5/p25considerably enhances phosphorylation of tau by GSK3β on other epitopes,also found hyperphosphorylated in Alzheimer's disease. Moreover,neurofibrillary tangles, the hallmark of Alzheimer's disease, arelabeled with antisera for GSK3β and cdk5, but not GSK3β and MAP kinase,also, GSK3β and cdk5 are associated with microtubules and both, morethan PKA and CK, contribute to the AD-like phosphorylation of tauprotein. These results taken together suggest that mixed inhibitors ofGSK3β and cdk5/p25 should efficient in protecting tau protein fromhyperphosphorylation. Therefore, they would be useful in the treatmentof any pathological disorder associated with the abnormalphosphorylation of tau protein, in particular Alzheimer's disease, butalso other taupathies (e.g. frontotemporoparietal dementia, corticobasaldegeneration, Pick's disease, progressive supranuclear palsy).

Cdk5/p25 has been linked to apoptosis and neurodegeneration in moregeneral terms. Its overexpression induces apoptosis in cultured neurons,in brain tissue apoptotic cells show strong immunoreactivity for cdk5.Neurotoxic agents, incl. Aβ(1-42), neuronal injury, ischemia or growthfactor withdrawal lead to activation and mislocalization of cdk5/p25,abnormal phosphorylation of cdk5 substrates, cytoskeletal disruption andcell death. Moreover, phosphorylation by cdk5/p25 transforms DARPP-32into an inhibitor of protein kinase A, reducing signal transduction inthe striatum with obvious implications for Parkinson's disease. A rolefor cdk5 in ALS has also been proposed based on its ability tophosphorylate neurofilaments. More recently, deregulation of cdk5 wasdetected in a mouse model of amyotrophic lateral sclerosis.

Altogether, these experimental observations indicate that GSK3βinhibitors may find application in the treatment of theneuropathological consequences and the cognitive and attention deficitsassociated with Alzheimer's disease, as well as other acute and chronicneurodegenerative diseases. These include, in a non-limiting manner,Parkinson's disease, taupathies (e.g. frontotemporoparietal dementia,corticobasal degeneration, Pick's disease, progressive supranuclearpalsy) and other dementia including vascular dementia; acute stroke andothers traumatic injuries; cerebrovascular accidents (e.g. age relatedmacular degeneration); brain and spinal cord trauma; peripheralneuropathies; retinopathies and glaucoma.

In addition GSK3β inhibition may find application in the treatment ofother diseases such as:

Non-insulin dependent diabetes (such as diabetes type II) and obesity;manic depressive illness; schizophrenia; alopecia; cancers such asbreast cancer, non-small cell lung carcinoma, thyroid cancer, T orB-cell leukemia and several virus-induced tumors.

Since it appears that both, GSK3β and cdk5/p25 play a major role in theinduction of apoptosis in neuronal cells, combined inhibition of thesetwo enzymes may find application in the treatment of not onlyAlzheimer's disease and the other above-mentioned taupathies, but alsoin a number of other neurodegenerative disorders, in particularParkinson's disease and amyotrophic lateral sclerosis; other dementiasincluding vascular dementia; acute stroke and other traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma.

In addition mixed TPK1/TPK2 inhibitors may find their applications inthe treatment of other diseases such as: smoking cessation and otherwithdrawal syndromes, epilepsy.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β or GSK3β and cdk5/p25activity, more particularly of neurodegenerative diseases. Morespecifically, the object is to provide novel compounds useful as anactive ingredient of a medicament that enables prevention and/ortreatment of neurodegenerative diseases such as Alzheimer's disease.

Thus, the inventors of the present invention have identified compoundspossessing inhibitory activity against GSK3β. As a result, they foundthat compounds represented by the following formula (I) had the desiredactivity and were useful as an active ingredient of a medicament forpreventive and/or therapeutic treatment of the aforementioned diseases.

The present invention thus provides pyrimidone derivatives representedby formula (I) or salts thereof, solvates thereof or hydrates

thereof:wherein:

-   X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a    C₁₋₂ alkyl group and a hydrogen atom;-   Y represents a bond, an ethenylene group, an ethynylene group or a    methylene group optionally substituted by one or two groups chosen    from a C₁₋₆ alkyl group, a hydroxy group or a C₁₋₄ alkoxy group;-   R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine    ring, the ring being optionally substituted by a C₃₋₆ cycloalkyl    group, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, a benzyl group or a    halogen atom;-   R2 represents a heterocyclic bicyclic rings, having 1-4 heteroatoms    selected from an oxygen atom, a sulfur atom and a nitrogen atom and    having 5-9 carbon atoms, of formula

wherein A, B, C and D represent, each independently, a carbon atom or anitrogen atom and W represent a saturated or unsaturated 5, 6 or 7membered cyclic ring having from 3 to 7 carbon atoms and 2 to 0heteroatoms such as an oxygen atom, a sulfur atom or a nitrogen atom;the R2 group being optionally substituted on a carbon atom or, whenpossible, on a nitrogen atom by one or two atoms or groups chosen from ahalogen atom, a C₁₋₆ alkyl group, a hydroxy group, a C₁₋₄ alkoxy group,a phenyl ring, a pyridine ring or a —NR6R7 group;

-   R3 represents a hydrogen atom, a C₁₋₆ alkyl group, a hydroxy group,    a C₁₋₄ alkoxy group or a halogen atom;-   R4 represents a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₄ alkoxy    group or a halogen atom;-   R5 represents a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₂    perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group or a    halogen atom;-   R6 and R7 represent, each independently, a hydrogen atom, a C₁₋₆    alkyl group, a benzyl group, a phenyl ring or R6 and R7 represent    together with the nitrogen atom, a pyrrolidine ring, a piperidine    ring, a hexamethyleneimine ring, a morpholine ring or a piperazine    ring, the rings being optionally substituted by one or two C₁₋₆    alkyl group;-   When m equals 0, p equals 1, 2 or 3,-   When m equals 1, p equals 0, 1 or 2,-   When m equals 2, p equals 0 or 1;-   When m equals 3, p equals 0;-   and-   n represents 0 to 3;    with the proviso that the derivative of formula (I) is not-   9-[2-(1H-indol-3-yl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   9-[3-(1H-indol-3-yl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one;-   1-[2-(1H-Indol-3-yl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one,    or-   1-[3-(1H-indol-3-yl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the pyrimidone derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby abnormal GSK3β or GSK3β and cdk5/p25 activity, and the aforementionedmedicament which is used for preventive and/or therapeutic treatment ofneurodegenerative diseases and in addition other diseases such as:

Non-insulin dependent diabetes (such as diabetes type II) and obesity;manic depressive illness; schizophrenia; alopecia; smoking cessation andother withdrawal syndromes, epilepsy; cancers such as breast cancer,non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia andseveral virus-induced tumors.

As further preferred embodiments of the present invention, there areprovided the aforementioned medicament wherein the diseases areneurodegenerative diseases and are selected from the group consisting ofAlzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,taupathies (e.g. frontotemporoparietal dementia, corticobasaldegeneration, Pick's disease, progressive supranuclear palsy) and otherdementia including vascular dementia; acute stroke and others traumaticinjuries; cerebrovascular accidents (e.g. age related maculardegeneration); brain and spinal cord trauma; peripheral neuropathies;retinopathies and glaucoma, and the aforementioned medicament in theform of pharmaceutical composition containing the above substance as anactive ingredient together with one or more pharmaceutical additives.

The present invention further provides an inhibitor of GSK3β or GSK3βand cdk5/p25 activity comprising as an active ingredient a substanceselected from the group consisting of the pyrimidone derivatives offormula (I) and the salts thereof, and the solvates thereof and thehydrates thereof.

According to further aspects of the present invention, there is provideda method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β or GSK3β andcdk5/p25 activity, which comprises the step of administering to apatient a preventively and/or therapeutically effective amount of asubstance selected from the group consisting of the pyrimidonederivatives of formula (I) and the physiologically acceptable saltsthereof, and the solvates thereof and the hydrates thereof; and a use ofa substance selected from the group consisting of the pyrimidonederivatives of formula (I) and the physiologically acceptable saltsthereof, and the solvates thereof and the hydrates thereof for themanufacture of the aforementioned medicament.

As used herein, the C₁₋₆ alkyl group represents a straight or branchedalkyl group having 1 to 6 carbon atoms, for example, methyl group, ethylgroup, n-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group,neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexylgroup, and the like;

The ethenylene group represents the divalent group of formula:

The ethynylene group represents the divalent group of formula:

The C₁₋₄ alkoxy group represents an alkyloxy group having 1 to 4 carbonatoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

The C₁₋₂ perhalogenated alkyl group represents an alkyl group whereinall of the hydrogen atoms have been substituted by a halogen atom, forexample a CF₃ or C₂F₅;

The C₁₋₃ halogenated alkyl group represents an alkyl group wherein atleast one hydrogen has not been substituted by a halogen atom;

The halogen atom represents a fluorine, chlorine, bromine or iodineatom.

The leaving group represents a group which could be easily cleaved andsubstituted, such a group may be for example a tosyloxy, a mesyloxy, abromide and the like.

The compounds represented by the aforementioned formula (I) may form asalt. Examples of the salt include, when an acidic group exists, saltsof alkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine, and arginine. The base-addition salts of acidiccompounds are prepared by standard procedures well known in the art.

When a basic group exists, examples include salts with mineral acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid; salts with organic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionicacid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid,succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid,lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinicacid, and salicylic acid; or salts with acidic amino acids such asaspartic acid, and glutamic acid.

The acid-addition salts of the basic compounds are prepared by standardprocedures well know in the art which include, but are not limitedthereto, dissolving the free base in an aqueous alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and an acid in an organicsolvent, in which case the salt separates directly, or is precipitatedwith a second organic solvent, or can be obtained by concentration ofthe solution. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, pharmaceutically-acceptable salts, that is, salts whoseanions are relatively innocuous to the animal organism in pharmaceuticaldoses of the salts, so that the beneficial properties inherent in thefree base are not compromised by side effects ascribable to the anions.Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention.

In addition to the pyrimidone derivatives represented by theaforementioned formula (I) and salts thereof, their solvates andhydrates also fall within the scope of the present invention. Thepyrimidone derivatives represented by the aforementioned formula (I) mayhave one or more asymmetric carbon atoms. As for the stereochemistry ofsuch asymmetric carbon atoms, they may independently be in either (R)and (S) configuration, and the pyrimidone derivative may exist asstereoisomers such as optical isomers, or diastereoisomers. Anystereoisomers in pure form, any mixtures of stereoisomers, racemates andthe like fall within the scope of the present invention.

Examples of preferred compounds of the present invention are shown intable 1A, 2A, 1B and 2B hereinafter. However, the scope of the presentinvention is not limited by these compounds.

Preferred compounds of the present invention represented by formula (I)include also compounds wherein:

-   (1) R1 represents a 3- or 4-pyridine ring and more preferably    4-pyridine ring or a 4- or 5-pyrimidine ring and more preferably    4-pyrimidine ring, which may be substituted by a C₁₋₂ alkyl group, a    C₁₋₂ alkoxy group or a halogen atom; and/or-   (2) X represents two hydrogen atoms, an oxygen atom or a C₁₋₂ alkyl    group and a hydrogen atom;-   (3) Y represents a bond or a methylene group optionally substituted    by one or two groups chosen from a C₁₋₃ alkyl group or a hydroxy    group; and/or-   (4) R2 represents a heterocyclic bicyclic rings, having 1-4    heteroatoms selected from an oxygen atom, a sulfur atom and a    nitrogen atom and having 5-9 carbon atoms, of formula

wherein A, B, C and D represent, each independently, a carbon atom or anitrogen atom and W represent a saturated or unsaturated 5, 6 or 7membered cyclic ring having from 3 to 7 carbon atoms and 2 to 0heteroatoms such as an oxygen atom, a sulfur atom or a nitrogen atom;the R2 group being optionally substituted on a carbon atom or, whenpossible, on a nitrogen atom by one or two atoms or groups chosen from ahalogen atom, a C₁₋₆ alkyl group, a hydroxy group, a C₁₋₄ alkoxy group,a phenyl ring, a pyridine ring or a —NR6R7 group;with the proviso that when R1 is a pyridine ring and R2 is an indolering; R3, R4 and R5 does not represent a hydrogen atom and (m+p) isdifferent of 1 or 2.

More preferred compounds of the present invention represented by formula(I) include also compounds wherein:

-   (1) R1 represents an unsubstituted 4-pyridine ring or a 4-pyrimidine    ring; and/or-   (2) X represents two hydrogen atoms; and/or-   (3) Y represents a bond; and/or-   (4) R3 and R4 represent each independently a hydrogen atom, a    halogen atom or a C₁₋₂ alkyl group; and/or-   (5)    -   R2 is a heterocyclic bicyclic ring of formula

wherein A, B, C and D represent, each independently, a carbon atom or anitrogen atom and T and U represent, each independently, a carbon atomor a heteroatom such as an oxygen atom, a sulfur atom or a nitrogen atomand s is 0 or 1; or

-   -   R2 is a heterocyclic bicyclic ring of formula

wherein A, B, C and D represent, each independently, a carbon atom or anitrogen atom and T and U represent, each independently, a carbon atomor a heteroatom such as an oxygen atom or a sulfur atom; or

-   -   The heterocyclic ring represented by R2 is a heterocyclic        bicyclic ring of formula

wherein A, B, C and D represent, each independently, a carbon atom or anitrogen atom and T and U represent, each independently, a carbon atomor a heteroatom such as a nitrogen atomwith the proviso that when R1 is a pyridine ring and R2 is an indolering; R3, R4 and R5 does not represent a hydrogen atom and (m+p) isdifferent of 1 or 2; preferably R2 represents a cyclopentapyrazin;6,7-dihydrocyclopentapyrazin; benzofuran, 2,3-dihydrobenzofuran;1,4-benzodioxan; 2,3-dihydro-benzo[1,4]dioxin; chromane; isochromane;quinoxaline; quinazoline; furopyridine; pyrindine or6,7-dihydropyrindine group; preferably a 6,7-dihydrocyclopentapyrazin,6,7-dihydropyrindine, benzofuran, 2,3-dihydrobenzofuran, chromane,2,3-dihydro-benzo[1,4]dioxin or furopyridine group; and more preferablycompounds wherein R1 and X and Y and R3 and R4 and R2 are defined asabove. Particularly preferred compounds of the present inventionrepresented by formula (I), wherein R1 is a pyridine ring, includecompounds of table 1A:

-   N^(o) 1.    (+)-(6R)-9-(6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 2.    (−)-(6S)-9-(6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 3.    (+)-(6R)-9-(6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 4.    (+/−)-7,7-Dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one.

N^(o) 5.(+)-7,7-Dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

-   N^(o) 6.    (−)-7,7-Dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]-pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 7.    (+/−)-9-(2,3-Dihydro-benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 8.    9-(Furo[3,2-b]pyridin-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 9.    9-(Benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 10.    (+/−)9-(2-Chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 11. (+/−)    7,7-Dimethyl-2-(pyridin-4-yl)-9-[2-(pyridin-4-yl)-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidine-4-one-   N^(o) 12. (+/−)    7,7-Dimethyl-9-(2-phenyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidine-4-one-   N^(o) 13. (+/−)    7,7-Dimethyl-2-(pyridin-4-yl)-9-[2-(pyrrolidin-1-yl)-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 14. (+/−)    7,7-Difluoro-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidine-4-one-   N^(o) 15.    9-((+)-(6-R)-6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-(+/−)-7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidine-4-one.

Particularly preferred compounds of the present invention represented byformula (I), wherein R1 is a pyridine ring, include also compounds oftable 2A:

-   N^(o) 1.    9-Chroman-2-ylmethyl-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 2.    9-(8-Methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 3.    9-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 4.    9-(5-Methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 5.    9-(6,7-Dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 6.    9-Chroman-2-ylmethyl-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 7.    9-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 8.    9-(5-Fluoro-8-methoxy-chroman-2-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 9.    9-Furo[3,2-b]pyridin-2-ylmethyl-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 10.    9-(6,7-Dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 11.    9-(6,7-Dihydro-5H-[2]pyrindin-6-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 12.    9-(6,7-Dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one.

Particularly preferred compounds of the present invention represented byformula (I), wherein R1 is a pyrimidine ring, include also compounds oftable 1B:

-   N^(o) 1.    9-(6,7-Dihydro-5H-cyclopentapyrazin-6-ylmethyl)-7,7-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 2. (+/−)    7,7-Dimethyl-2-(pyrimidin-4-yl)-9-(2-phenyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidine-4-one-   N^(o) 3.    (+/−)9-(2-Chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 4.    (+/−)-9-(Chroman-3-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 5.    (+/−)-9-(6,7-Dihydro-5H-[2]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 6.    (−)-(S)-9-(2,3-Dihydro-benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 7.    (+/−)9-(5-Fluoro-8-methoxy-chroman-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 8.    (+/−)9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 9.    (+/−)-9-(5-Methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 10.    (−)-(6S)-9-(6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 11.    (+)-(6R)-9-(6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 12.    9-(2-Furo[2,3-b]pyridin-3-yl-ethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 13.    9-Benzofuran-2-ylmethyl-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 14.    (+/−)-7,7-Dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6ylmethyl)-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one.

Particularly preferred compounds of the present invention represented byformula (I), wherein R1 is a pyrimidine, include also compounds of table2B:

-   N^(o) 1.    9-(8-Methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 2.    9-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 3.    9-Chroman-2-ylmethyl-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 4.    9-(5-Fluoro-8-methoxy-chroman-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 5.    9-(5-Fluoro-8-methoxy-chroman-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 6.    9-Chroman-2-ylmethyl-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 7.    9-(8-Methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 8.    9-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 9.    9-(5-Methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 10.    9-(5-Methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 11.    9-(6,7-Dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 12.    9-(6,7-Dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 13.    9-(6,7-Dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 14.    9-Furo[3,2-b]pyridin-2-ylmethyl-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 15.    9-(6,7-Dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one-   N^(o) 16.    9-(6,7-Dihydro-5H-[2]pyrindin-6-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one.

As a further object, the present invention concerns also methods forpreparing the compounds represented by the aforementioned formula (I).These compounds can be prepared, for example, according to methodsexplained below.

Preparation Method

Pyrimidone compounds represented by the aforementioned formula (I) maybe prepared according to scheme 1.

(In the above scheme the definition of R1, R2, R3, R4, R5, X, Y, p, mand n are the same as those already described for compound of formula(I)).

The pyrimidinone derivative represented by the above formula (III),wherein R1 is as defined for compound of formula (I), is allowed toreact with a base such as sodium hydride, sodium carbonate or potassiumcarbonate in a solvent such as N,N-dimethylformamide,N-methylpyrrolidine, N,N-dimethylacetamide or chloroform at a suitabletemperature ranging from 0 to 130° C. under ordinary air, then with acompound of formula (II), wherein R2, X, Y and n are as defined forcompound of formula (I) and L represents a leaving group preferablybromide or mesyloxy group, is added to obtain the compound of theaforementioned formula (I).

Compound of formula (II) are commercially available or may besynthesized according to well-known methods of one skilled in the art.For example compounds of formula (II) can be prepared by analogy to themethod described in U.S. Pat. No. 5,559,256.

As another example compounds of formula (II) wherein

-   -   X represents two hydrogen atoms,    -   L represents a leaving group,    -   n is 1,    -   Y represents a bond, and    -   R2 represents a heterocyclic bicyclic ring of formula:

may be prepared by analogy to the method described in U.S. Pat. No.4,957,928 or U.S. Pat. No. 5,137,901; orwherein

-   -   R2 represents a heterocyclic bicyclic ring of formula

-   -   -   wherein A, B, C and D are defined as above,        -   T and U represent each a carbon atom        -   and s is 0;            may be prepared by analogy to the method described in            WO99/02517 or to scheme 2.

According to the method described in scheme 2, the di-acid of formula(XI), is firstly esterified, for example by action of thionyl chloridein an alcoholic solvent such as ethanol, and then immediately reduced byaction of sodium borohydride in the presence of calcium carbonate togive the compound of formula (X). Compound (X) is allowed to react withthionylchloride to give the corresponding bi-chloride compound offormula (IX) which is then transformed into the diester of formula(VIII) by reaction with the sodium dianion derivative ofdiethylmalonate, in a solvent such as ethanol. Compound (VIII) is thensaponified by action of concentrated potassium hydroxide in an alcoholicsolvent such as ethanol, neutralized by addition of concentratedhydrochloric acid, decarboxylated by heating and then esterified bytreatment with a solution of hydrochloric acid in ethanol, to givecompound (VII). The ester (VII) can be separated into its enantiomersusing methods well known by one skilled in the art, such as for example,enzymatic way or chemical separation.

The ester of formula (VII) can then be reduced into an alcohol offormula (VI), using for example lithium aluminum hydride in a solventsuch as tetrahydrofuran. The hydroxy group is transformed into a leavinggroup. For example, the alcohol is allowed to react withtriphenylphosphine dibromide in a solvent such as dioxane to givecompound (II) as defined above, wherein L represent a bromide atom.

The compound of formula (III) may be prepared according to the methoddefined in scheme 3.

(In the above scheme the definition of R1, R3, R4, R5, p and m are thesame as already described.)

According to this method, the 3-ketoester of formula (IV), wherein R1and R5 are as defined for compound of formula (I) and R is an alkylgroup such as for example methyl or ethyl, is allowed to react with acompound of formula (V). The reaction may be carried out in the presenceof potassium carbonate, in an alcoholic solvent such as methanol,ethanol and the like or without, at a suitable temperature ranging from250 to 140° C. under ordinary air.

Alternatively, compounds of formula (III) wherein R5 represents ahydrogen atom may be halogenated in order to give compounds of formula(III) wherein R5 is a halogen atom such as a bromine atom or a chlorineatom.

The reaction may be carried out in an acidic medium such as acetic acidor propionic acid, in presence of bromosuccinimide or chlorosuccinimide,or bromine.

In addition, compounds of formula (III) wherein R5 represents a fluorineatom may be obtained by analogy to the method described in TetrahedronLetters, Vol. 30, N^(o) 45, pp 6113-6116, 1989.

Compounds of formula (V) or (IV) are commercially available or may besynthesized according to well-known methods of one skilled in the art.

For example compounds of formula (IV), wherein R1 represent a pyridinering or a pyrimidine ring, optionally substituted by a C₁₋₄ alkyl group,C₁₋₄ alkoxy group or a halogen atom, can be prepared by reactingrespectively an isonicotinic acid or a pyrimidine-carboxylic acid,optionally substituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxy group or ahalogen, with the corresponding malonic acid monoester. The reaction canbe carried out using methods well known to one skilled in the art, suchas for example in presence of a coupling agent such as1,1′-carbonylbis-1H-imidazole in a solvent such as tetrahydrofuran at atemperature ranging from 20 to 70° C.

Compounds of formula (I) may also be obtained starting from anothercompound of formula (I) using well-known methods of one skilled in theart.

In the above reactions, protection or deprotection of a functional groupmay sometimes be necessary. A suitable protecting group Pg can be chosendepending on the type of the functional group, and a method described inthe literature may be applied. Examples of protecting groups, ofprotection and deprotection methods are given for example in Protectivegroups in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons,Inc., New York).

The compounds of the present invention have inhibitory activity againstGSK3β. Accordingly, the compounds of the present invention are useful asan active ingredient for the preparation of a medicament, which enablespreventive and/or therapeutic treatment of a disease caused by abnormalGSK3β or GSK3β and cdk5/p25 activity and more particularly ofneurodegenerative diseases such as Alzheimer's disease. In addition, thecompounds of the present invention are also useful as an activeingredient for the preparation of a medicament for preventive and/ortherapeutic treatment of neurodegenerative diseases such as Parkinson'sdisease, amyotrophic lateral sclerosis, taupathies (e.g.frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma; and other diseases such as non-insulin dependent diabetes(such as diabetes type II) and obesity; manic depressive illness;schizophrenia; alopecia; smoking cessation and other withdrawalsyndromes, epilepsy; cancers such as breast cancer, non-small cell lungcarcinoma, thyroid cancer, T or B-cell leukemia and severalvirus-induced tumors.

The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β or GSK3βand cdk5/p25 and of the aforementioned diseases which comprisesadministering to a mammalian organism in need thereof an effectiveamount of a compound of the formula (I).

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention, however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances, or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatine.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be 0.01to 1,000 mg (the weight of an active ingredient), and the dose may beadministered once a day or several times a day as divided portions, oronce in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001 to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES

The present invention will be explained more specifically with referenceto the following general examples, however, the scope of the presentinvention is not limited to these examples.

Part A—R1=Pyridine Ring (Tables 1A and 2A)

Example 1 (Compound N^(o) 1 of Table 1A)(+)-(6R)-9-(6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one1.17,7-Dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

A mixture of 5.9 g (30.55 mmol) of ethyl 3-(4-pyridyl)-3-oxopropionate,5.0 g (30.55 mmol) of 5,5-dimethyl-1,4,5,6-tetrahydro-2-pyrimidinaminemonohydrochloride (prepared by analogy to U.S. Pat. No. 4,262,122) and6.33 g (45.82 mmol) of potassium carbonate in 60 ml of ethanol washeated at reflux temperature during 12 h. The cooled suspension wasfiltered and the solvent removed by evaporation. The residue obtainedwas dissolved in dichloromethane and washed with water. The organicphase was dried and evaporated to give 6.30 g (80%) of product as abeige solid. Mp.: 152-154° C.

1.2(−)-(6R,5R)-(6,7-Dihydro-5H-[1]pyrindin-6-yl)-(10,10-dimethyl-3,3-dioxa-3-thia-4-aza-tricyclo[5.2.1.0<1,5>]dec-4-yl]-methanone

A suspension of 12 g (73.56 mmol) of(+/−)-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid (prepared by analogywith WO 99/02517) in 85 ml of anhydrous dimethylformamide was treatedwith 13.36 g (82.39 mmol) of 1,1′-carbonyldiimidazole and the resultingmixture was heated at 45° C. for 1 h. 15.84 g (73.56 mmol) of(−)-10,2-camphorsultam (Fluka) and 11.2 g (73.56 mmol) of1,8-diazabicyclo[5,4,0]undec-7-ene were added and the reaction mixturewas stirred at 40° C. for 18 h. The precipitated solid was recovered byfiltration, washed with ethyl acetate, diethyl ether and dried,affording 20.8 g (79%) of product as a white solid.

Mp.: 270-272° C. [α]_(D) ²⁰=−151° (c=1, CHCl₃).

1.3 (+)-(6R)-6,7-Dihydro-5H-[1]pyrindine-6-carboxylic acid

To a solution of 20.6 g (57.15 mmol) of(−)-(6R,5R)-(6,7-Dihydro-5H-[1]pyrindin-6-yl)-(10,10-dimethyl-3,3-dioxa-3-thia-4-aza-tricyclo-[5.2.1.0<1,5>]dec-4-yl]-methanonein 300 ml of tetrahydrofuran/water in the proportions 2:1 was added 2.88g (68.6 mmol) of lithium hydroxide. The mixture was allowed to stir atroom temperature for 5 h. Water was added, and the reaction mixture wasextracted with ethyl acetate. The aqueous phase was acidified to pH 6with acetic acid. The precipitate obtained was filtered off and dried togive 7.5 g (81%) of white solid. Mp.: 236-237 [α]_(D) ²⁰=+5.4° (c=0.5,dimethylformamide).

1.4 (+)-(6R)-(6,7-Dihydro-5H-[1]pyrindin-6-yl)-methanol

To a solution of 3.269 (20 mmol) of(+)-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid in 100 ml of anhydroustetrahydrofuran under argon was added 1.149 (30 mmol) of lithiumaluminum hydride. The resulting mixture was stirred at room temperaturefor 1 h. Excess of lithium aluminum hydride was hydrolyzed with 4.56 mlof water and 1.14 ml of sodium hydroxide (15%). The precipitate wasfiltered off and washed with diethyl ether, the filtrate was evaporatedto give 2.88 g (97%) of product as an oil. [α]_(D) ²⁰=+6.20 (c=0.75,CH₂Cl₂).

1.5 Methanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-6-ylmethyl ester

To a solution of 895 mg (6 mmol) of(+)-(6R)-(6,7-dihydro-5H-[1]pyrindin-6-yl)-methanol in 50 ml ofanhydrous dichloromethane was added at −15° C. 0.918 ml (6.6 mmol) oftriethylamine and 0.465 ml (6 mmol) of methanesulfonyl chloride. Theresulting mixture was stirred at 0° C. for 45 min. The mixture was thendiluted with water and dichloromethane and extracted withdichloromethane. Organic layer was dried and evaporated to give 1.4 g(100%) of methanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-6-ylmethylester.

1.6(+)-(6R)-9-(6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

A suspension of 0.51 g (2 mmol) of7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onein 10 ml of anhydrous dimethylformamide was treated with 96 mg (2 mmol)of sodium hydride (50% suspension in mineral oil) and the resultingmixture was stirred for 40 min. 0.455 g (2 mmol) of methanesulfonic acid6,7-dihydro-5H-[1]pyrindin-6-ylmethyl ester in 2 ml of anhydrousdimethylformamide was added and the reaction mixture stirred at roomtemperature for 18 h. The solution was treated with water and extractedwith ethyl acetate. The organic phase was dried and evaporated to givecrude product, which was purified by silica gel chromatography, elutingwith ethyl acetate/methanol/diethyl amine in the proportions 98/2/0.2 togive 0.3839 of pure product obtained in the form of free base. Mp:182-184° C. [α]_(D) ²⁰=+9.15° (c=0.5, CH₂Cl₂).

Example 2 (Compound N^(o) 2 of Table 1A)(−)-(6S)-9-(6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

2.1 By analogy with the method described in example 1, using(+)-10,2-camphorsultam (Fluka) in place of (−)-10,2-camphorsultam instep 1.2, the compound was obtained as a free base. Mp.: 182-185° C.[α]_(D) ²⁰=−6.60 (c=0.5, CH₂Cl₂).

Example 3 (Compound N^(o) 3 of Table 1A)(+)-(6R)-9-(6,7-Dihydro-5H-[1]pyrindin-6ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one3.1.2-(Pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

A mixture of 8.98 g (46.5 mmol) of ethyl 3-(4-pyridyl)-3-oxopropionateand 8.0 g (46.5 mmol) of 2-amino-3,4,5,6-tetrahydropyrimidinedihydrochloride (prepared according to J. Org. Chem. 1955, 20, 829.) and19.3 g (139.5 mmol) of potassium carbonate in 60 ml of ethanol washeated at reflux temperature during 18 h. The solution cooled, wasevaporated to remove solvent. The residue was treated with water andextracted with dichloromethane. The extracts were dried and evaporatedto give 8.0 g (75%) of product as a white powder. Mp: 219° C.

3.2(+)-(6R)-9-(6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

A suspension of 0.46 g (2 mmol) of2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in10 ml of anhydrous dimethylformamide was treated with 96 mg (2 mmol) ofsodium hydride (50% suspension in mineral oil) and the resulting mixturewas stirred for 40 min. 0.455 g (2 mmol) of methanesulfonic acid6,7-dihydro-5H-[1]pyrindin-6-ylmethyl ester in 2 ml of anhydrousdimethylformamide was added and the reaction mixture stirred at 45° C.for 18 h. The solution was treated with water and extracted with ethylacetate. The organic phase was dried and evaporated to give crudeproduct, which was purified by silica gel chromatography, eluting withethyl acetate/methanol/ammonia in the proportions 90/10/1 to give 0.373g of pure product obtained in the form of free base. Mp: 174-175° C.[α]_(D) ²⁰=+10.50 (c=1, CH₂Cl₂).

Example 4 (Compound N^(o) 4 of Table 1A)(+/−)-7,7-Dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]-pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

By analogy with the method described in example 1, using(+/−)2-methyl-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid instead of(+/−)-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid, the compound wasobtained as a free base. Mp.: 140-141° C.

Example 5 (Compound N^(o) 5 of Table 1A)(+)-7,7-Dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]-pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

180 mg (0.45 mmol) of(+/−)-7,7-Dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]-pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one(compound N^(o) 4) was separated by chiral preparative HPLC (CHIRALCELOD 250×20) eluting with heptane/ethanol/diethylamine in the proportions85/15/0.1 to give 0.071 g of pure product obtained in the form of freebase. t_(R): 12.48 min. Mp: 94-96° C. [α]_(D) ²⁰=+6.79° (c=0.5, CH₂Cl₂).

Example 6 (Compound N^(o) 6 of Table 1A)(−)-7,7-Dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]-pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

180 mg (0.45 mmol) of(+/−)-7,7-Dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]-pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one(compound N^(o) 4) was separated by chiral preparative HPLC (CHIRALCELOD 250×20) eluting with heptane/ethanol/diethylamine in the proportions85/15/0.1 to give 0.075 g of pure product obtained in the form of freebase. t_(R): 17.25 min. Mp: 94-96 C. [α]_(D) ²⁰=−5.61° (c=0.5, CH₂Cl₂).

Example 7 (Compound N^(o) 7 of Table 1A)(+/−)-9-(2,3-Dihydro-benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

A suspension of 0.51 g (2 mmol) of7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onein 10 ml of anhydrous dimethylformamide was treated with 96 mg (2 mmol)of sodium hydride (50% suspension in mineral oil) and the resultingmixture was stirred at 40° C. for 40 min. 0.52 g (2 mmol) of(+/−)2-iodomethyl-2,3-dihydro-benzofuran (prepared according toSynthesis 1997, (1), 23-25) in 2 ml of anhydrous dimethylformamide wasadded and the reaction mixture stirred at 60° C. for 20 min. Thesolution was treated with water and extracted with ethyl acetate. Theorganic phase was dried and evaporated to give crude product, which waspurified by silica gel chromatography, eluting withdichloromethane/methanol/ammonia in the proportions 99/1/0.1 to 98/2/0.2to give 0.171 g of pure product obtained in the form of free base. Mp:147-149° C.

Example 8 (Compound N^(o) 8 of Table 1A)9-(Furo[3,2-b]pyridin-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one8.1 Methanesulfonic acid furo[3,2-b]pyridin-2-ylmethyl ester

The product was obtained by analogy with the method described in step1.5 and using furo[3,2-b]pyridin-2-yl-methanol (U.S. Pat. No. 5,559,256or EP 580402) and was used as such in the next step.

8.29-Furo[3,2-b]pyridin-2-ylmethyl-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

By analogy with the method described in step N^(o) 1.6, usingmethanesulfonic acid furo[3,2-b]pyridin-2-ylmethyl ester, the compoundwas obtained in the form of free base. Mp: 170-171° C.

Example 9 (Compound N^(o) 10 of Table 1A)(+/−)-9-(2-Chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9.1 (+/−) (2-Chloro-6,7-dihydro-5H-[1]pyrindin-6-yl)-methanol

To a solution of 1.83 g (9.26 mmol) of(+/−)2-chloro-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid (prepared byanalogy to the method described in WO 99/02517) in 50 ml of anhydroustetrahydrofuran under argon was added 0.52 g (13.89 mmol) of lithiumaluminum hydride. The resulting mixture was stirred at room temperaturefor 2 h. Excess of lithium aluminum hydride was hydrolyzed with 2.13 mlof water and 0.53 ml of sodium hydroxide (15%). The precipitate wasfiltered off and washed with diethyl ether, the filtrate was evaporatedto give 1.61 g (95%) of product as an oil.

9.2 (+/−)Methanesulfonic acid2-chloro-6,7-dihydro-5H-[1]pyrindin-6-yl-methyl ester

The product was obtained by analogy with the method described in step1.5 and using (+/−)(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-yl)-methanol.The product was used as such in the next step.

9.3(+/−)9-(2-Chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with the method described in stepN^(o) 1.6, using (+/−)methanesulfonic acid2-chloro-6,7-dihydro-5H-[1]pyrindin-6-yl-methyl ester. The compound wasobtained in the form of free base. Mp: 180-181° C.

Example 10 (Compound N^(o) 11 of Table 1A) (+/−)7,7-Dimethyl-2-(pyridin-4-yl)-9-[2-(pyridin-4-yl)-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidine-4-one

To a solution of 0.22 g (0.521 mmol) of(+/−)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onein 3 ml of anhydrous toluene and 0.5 ml of ethanol was treated with0.625 ml (2M solution in water) of sodium carbonate, 36 mg (0.03 mmol)of tetrakis(triphenylphosphine)palladium and 0.096 g (0.781 mmol) ofpyridine-4-boronic acid. After being stirred for 24 h at 140° C., waterwas added, the mixture was extracted with dichloromethane. The organicphase was dried and evaporated to give crude product, which was purifiedby silica gel chromatography, eluting withdichloromethane/methanol/ammonia in the proportions 99/1/0.1 to give0.049 g of pure product obtained in the form of free base. Mp: 170-171°C.

Example 11 (Compound N^(o) 13 of Table 1A) (+/−)7,7-Dimethyl-2-(pyridin-4-yl)-9-[(2-pyrrolidin-1-yl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)]-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

To a solution of 0.2 g (0.474 mmol) of(+/−)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onein 20 ml of anhydrous pyrrolidine was treated with 0.216 g (0.664 mmol)of cesium carbonate, 8.85 mg (0.142 mmol) of(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 6.5 mg (0.07mmol) of tris(dibenzylideneacetone)dipalladium(0). After being stirredunder reflux for 24 h, water was added, the mixture was extracted withdichloromethane. The organic phase was dried and evaporated to givecrude product, which was purified by silica gel chromatography, elutingwith dichloromethane/methanol/ammonia in the proportions 99/1/0.1 togive 0.184 g of pure product obtained in the form of free base. Mp:170-171° C.

Example 12 (Compound N^(o) 14 of Table 1A) (+/−)7,7-Difluoro-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidine-4-onehydrochloride (1:2) 12.15,5-Difluoro-1,4,5,6-tetrahydro-2-pyrimidinamine

The product was obtained by analogy with the method described in U.S.Pat. No. 4,262,122 and using 2,2-difluoro-1,3-propandiamine (Tetrahedron(1994) 50(29), 8617-8632) and was used as such in the next step.

12.27,7-Difluoro-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with step N^(o) 3.1 and using5,5-difluoro-1,4,5,6-tetrahydro-2-pyrimidinamine from step 12.1. Mp:239-240° C.

12.3 (+/−)7,7-Difluoro-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidine-4-onehydrochloride (1:2)

The product was obtained by analogy with the method described in stepN^(o) 1.6 the compound was obtained in the form of free base which wastransformed into the hydrochloride salt. Mp: 236-238° C.

Example 13 (Compound N^(o) 15 of Table 1A)9-((+)-(6-R)-6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidine-4-one13.1 5-Methyl-1,4,5,6-tetrahydro-2-pyrimidinamine hydrochloride

To a solution containing 6.7 g (41.6 mmol) of2-methyl-1,3-propanediamine hydrochloride (Tetrahedron (1994) 50(29),8617-8632) in 50 ml of methanol was added 83 ml of a solution of sodiummethylate in methanol (1 mmol/ml) and the resulting mixture was treatedwith 3.97 g (41.6 mmol) of guanidine hydrochloride. The reaction mixturewas heated at 140° C. for 3 h. The solution was filtered, the solventevaporated and the residue obtained was used directly in the next step.

13.2(+/−)-7-Methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2a]pyrimidin-4-one

The product was obtained by analogy with step N^(o) 3.1 and using theintermediate from step N^(o) 13.1.

13.39-((+)-(6-R)-6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-7-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidine-4-one

The product was obtained by analogy with the method described in stepN^(o) 1.6, using(+/−)-7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one.The compound was obtained in the form of free base. Mp: 156-157° C.

Example 14 (Compound No. 10 of Table 2A)9-(6,7-Dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one14.18-Methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

A mixture of 6 g (31.0 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate,4.6 g (31.0 mmol) of 6-methyl-1,4,5,6-tetrahydro-pyrimidin-2-ylaminehydrochloride (prepared according to J. Org. Chem., 20, 1955, 829-838)and 6.44 g (46.0 mmol) of potassium carbonate in 50 ml of ethanol washeated at reflux temperature during 18 h. The reaction mixture wascooled and the solvent removed by evaporation. The residue obtained wastreated with water and the precipitate recovered by filtration to give3.85 g (51%) of product. Mp.: 245-247° C.

14.29-(6,7-Dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

To a solution of 0.15 g (0.62 mmol) of8-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onein 3 ml of anhydrous dimethylformamide was added 0.032 g (0.81 mmol) ofsodium hydride (60% suspension in mineral oil). The mixture was allowedto stir at 50° C. for 30 min. 0.184 g (0.81 mmol) of methanesulfonicacid 6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl ester was added and thestirring continued at 85° C. for 18 h. Water was added and the mixtureextracted with trichloromethane/methanol 90/10. The extracts were washedwith a saturated aqueous solution of sodium chloride, dried andevaporated to give crude product. Purification by chromatography onsilica gel, eluting with a mixture of ethyl acetate/ethanol in theproportions 100/0 to 74/26, gives 0.14 g (60%) of the compound in theform of free base. Mp.: 164-166° C.

Example 15 (Compound No. 5 in Table 2A)9-(6,7-Dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one15.18,8-Dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

A mixture of 7.68 g (39.8 mmol) of ethyl3-(pyridin-4-yl)-3-oxopropionate, 7.9 g (37.9 mmol) of6,6-dimethyl-1,4,5,6-tetrahydro-pyrimidin-2-ylamine hydrobromide(prepared according to Bull. Soc. Chim. Belg., 1950, 59, 573-587) and 11g (79.5 mmol) of potassium carbonate in 80 ml of ethanol were heated atreflux temperature during 18 h. The reaction mixture was cooled and thesolvent removed by evaporation. The residue obtained was treated withwater and the precipitate recovered by filtration to give 3.21 g (33%)of product.

15.29-(6,7-Dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

To a solution of 0.226 g (0.88 mmol) of8,8-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onein 5 ml of anhydrous dimethylformamide was added 0.040 g (0.97 mmol) ofsodium hydride (60% suspension in mineral oil) and the mixture wasallowed to stir at 45° C. for 3 hours. 0.20 g (0.88 mmol) ofmethanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl ester wasadded and the stirring continued at 80° C. for 18 h. The mixture wascooled and a solution of saturated ammonium chloride was added. Themixture was extracted with trichloromethane/methanol 90/10. The extractswere washed with a saturated aqueous solution of sodium chloride, driedand evaporated to give crude product. Purification by chromatography onsilica gel eluting with a mixture of ethyl acetate/ethanol in theproportions 100/0 to 70/20, gives 0.197 g (58%) of the compound in theform of free base. Mp.: 202-204° C.

A list of chemical structures and physical data for compounds of theaforementioned formula (I), wherein R1 is a pyridine ring, illustratingthe present invention is given in table 1A and 2A. The compounds havebeen prepared according to the methods of the examples.

In the tables:

(rac.) means racemic mixture

(−) means levo isomer

(+) means dextro isomer

(R) means absolute R configuration

(S) means absolute S configuration

In the tables 1A and 2A, R1 is an unsubstituted 4-pyridine ring (4-py);in the column “X”, when X represents two hydrogen atoms, only “H” isindicated and for compounds of formula (I) “m” and “p” equal 1.

TABLE 1A (I)

N° X Y R2 R3 R4 R5 n Mp ° C. salt 1 H bond

CH₃ CH₃ H 0 182-184 Free base 2 H bond

CH₃ CH₃ H 0 182-185 Free base 3 H bond

H H H 0 174-175 Free base 4 H bond

CH₃ CH₃ H 0 140-141 Free base 5 H bond

CH₃ CH₃ H 0 94-96 Free base 6 H bond

CH₃ CH₃ H 0 94-96 Free base 7 H bond

CH₃ CH₃ H 0 147-149 Free base 8 H bond

CH₃ CH₃ H 0 170-171 Free base 9 H bond

CH₃ CH₃ H 0 176-177 Free base 10 H bond

CH₃ CH₃ H 0 180-181 Free base 11 H bond

CH₃ CH₃ H 0 170-171 Free base 12 H bond

CH₃ CH₃ H 0 165-168 Free base 13 H bond

CH₃ CH₃ H 0 170-171 Free base 14 H bond

F F H 0 236-238 (1:2) hydrochloride 15 H bond

H CH₃ (Rac.) H 0 156-157 Free base

TABLE 2A (I)

N° X Y R2 R3 R4 R5 n Mp ° C. salt 1 H bond

H CH₃ (Rac.) H 0 178-180 Free base 2 H bond

H CH₃ (Rac.) H 0 258-260 (1:1) hydrochloride 3 H bond

H CH₃ (Rac.) H 0 164-166 Free base 4 H bond

H CH₃ (Rac.) H 0 146-148 Free base 5 H bond

CH₃ CH₃ H 0 202-204 Free base 6 H bond

CH₃ CH₃ H 0 169-171 (1:1) hydrochloride 7 H bond

CH₃ CH₃ H 0 151-153 Free base 8 H bond

CH₃ CH₃ H 0 211-213 Free base 9 H bond

H CH₃ (Rac.) H 0 137-139 (2:1) hydrochloride 10 H bond

H CH₃ (Rac.) H 0 164-166 Free base 11 H bond

H CH₃ (Rac.) H 0 146-148 Free base 12 H bond

H CH₃ (Rac.) H 0 173-175 Free basePart B−R1=Pyrimidine Ring (Tables 1B and 2B)

Example 1 (Compound N^(o) 1 of Table 1B)9-(6,7-Dihydro-5H-cyclopentapyrazin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9tetrahydro-pyrimido[1,2-a]pyrimidin-4-one1.17,7-Dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one

A mixture containing 5.15 g (26.52 mmol) of ethyl3-(4-pyrimidinyl)-3-oxopropionate, (prepared by analogy to the methoddescribed in patent DE 2705582), 4.34 g (26.52 mmol) of5,5-dimethyl-1,4,5,6-tetrahydro-2-pyrimidinamine monohydrochloride(prepared by analogy to the method described in U.S. Pat. No. 4,262,122)and 3.66 g (26.5 mmol) of potassium carbonate in 60 ml of methanol wereheated at reflux temperature during 18 h.

The cooled reaction mixture was evaporated and water was added. Theresulting precipitate was recovered by filtration and dried to give 4.86g (71%) of product. Mp.: 194-196° C.

1.2 (6,7-Dihydro-5H-cyclopentapyrazin-6-yl)-methanol

To a solution of 4.5 g (23.4 mmol) of6,7-dihydro-5H-cyclopentapyrazine-6 carboxylic acid ethyl ester(prepared by analogy to the method described in WO99/02517) in 90 ml ofanhydrous tetrahydrofuran under argon was added 1.33 g (35.1 mmol) oflithium aluminum hydride. The resulting mixture was stirred at roomtemperature for 2 h. The reaction mixture was diluted with 100 ml ofdiethyl ether at 0° C. and treated with excess of a saturated aqueoussolution of sodium sulfate. Further solid sodium sulfate was added andthe organic phase was filtered to remove salts. The solvent wasevaporated to dryness to give 3.3 g (94%) of product as an oil.

1.3 Methanesulfonic acid 6,7-dihydro-5H-cyclopentapyrazin-6-ylmethylester

To a solution of 1.3 g (8.7 mmol) of(6,7-dihydro-5H-cyclopentapyrazin-6-yl)-methanol in 15 ml of anhydrousdichloromethane was added at −15° C. 1.33 ml (9.52 mmol) oftriethylamine and 0.74 ml (9.52 mmol) of methanesulfonyl chloride. Theresulting mixture was stirred at 0° C. for 1 h. The mixture was thendiluted with water and dichloromethane and extracted withdichloromethane. Organic layer was dried and evaporated to give 1.73 g(88%) of methanesulfonic acid6,7-dihydro-5H-cyclopentapyrazin-6-ylmethyl ester.

1.49-(6,7-Dihydro-5H-cyclopentapyrazin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

A suspension of 0.5 g (1.94 mmol) of7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onein 10 ml of anhydrous dimethylformamide was treated with 155 mg (3.89mmol) of sodium hydride (50% suspension in mineral oil) and theresulting mixture was stirred for 40 min at 50° C. 0.888 g (3.89 mmol)of methanesulfonic acid 6,7-dihydro-5H-cyclopentapyrazin-6-ylmethylester in 2 ml of anhydrous dimethylformamide was added and the reactionmixture stirred at room temperature for 18 h. The solution was treatedwith water and extracted with ethyl acetate. The organic phase was driedand evaporated to give crude product, which was purified by silica gelchromatography, eluting with dichloromethane/methanol in the proportions100/1 to 95/5 to give 80 mg of pure product obtained in the form of freebase which was transformed into the hydrochloride salt. Mp: 193-195° C.

Example 2 (Compound N^(o) 11 of Table 1B)(+)-(6R)-9-(6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one2.1(−)-(6R,5R)-(6,7-Dihydro-5H-[1]pyrindin-6-yl)-(10,10-dimethyl-3,3-dioxa-3-thia-4-aza-tricyclo[5.2.1.0<1,5>]dec-4-yl]-methanone

A suspension of 12 g (73.56 mmol) of (+/−) 6,7-dihydro-5H-[1]pyrindine-6Carboxylic acid (prepared by analogy to the method described inWO99/02517) in 85 ml of anhydrous dimethylformamide was treated with13.36 g (82.39 mmol) of 1,1′-carbonyldiimidazole and the resultingmixture was heated at 45° C. for 1 h. 15.84 g (73.56 mmol) of(−)-10,2-camphorsultam (Fluka) and 11.2 g (73.56 mmol) of1,8-diazabicyclo[5,4,0]undec-7-ene were added and the reaction mixturewas stirred at 40° C. for 18 h. The precipitate solid was recovered byfiltration, washed with ethyl acetate, diethyl ether and dried affording20.8 g (79%) of product as a white solid. Mp.: 270-272° C. [α]_(D)²⁰=−151° (c=1, CHCl₃).

2.2 (+)-(6R)-6,7-Dihydro-5H-[1]pyrindine-6-carboxylic acid

To a solution of 20.6 g (57.15 mmol) of(−)-(6R,5R)-(6,7-dihydro-5H-[1]pyrindin-6-yl)-(10,10-dimethyl-3,3-dioxa-3-thia-4-aza-tricyclo[5.2.1.0<1,5>]dec-4-yl]-methanonein 300 ml of tetrahydrofuran/water in the proportions 2:1 was added 2.88g (68.6 mmol) of lithium hydroxide. The mixture was allowed to stir atroom temperature for 5 h. Water was added, and the reaction mixture wasextracted with ethyl acetate. The aqueous phase was acidified to pH 6with acetic acid. The precipitate obtained was filtered off and dried togive 7.5 g (81%) of white solid. Mp.: 236-237 [α]_(D) ²⁰=+5.40 (c=0.5,dimethylformamide).

2.3 (+)-(6R)-(6,7-Dihydro-5H-[1]pyrindin-6-yl)-methanol

To a solution of 3.26 g (20 mmol) of(+)-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid in 100 ml of anhydroustetrahydrofuran under argon was added 1.14 g (30 mmol) of lithiumaluminum hydride. The resulting mixture was stirred at room temperaturefor 1 h. Excess of lithium aluminum hydride was hydrolyzed with 4.56 mlof water and 1.14 ml of sodium hydroxide (15%). The precipitate wasfiltered off and washed with diethyl ether, the filtrate was evaporatedto give 2.88 g (97%) of product as an oil. [α]_(D) ²⁰=+6.2° (c=0.75,CH₂Cl₂).

2.4 Methanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-6-ylmethyl ester

To a solution of 895 mg (6 mmol) of(+)-(6R)-(6,7-dihydro-5H-[1]pyrindin-6-yl)-methanol in 50 ml ofanhydrous dichloromethane was added, at −15° C., 0.918 ml (6.6 mmol) oftriethylamine and 0.465 ml (6 mmol) of methanesulfonyl chloride. Theresulting mixture was stirred at 0° C. for 45 min. The mixture was thendiluted with water and dichloromethane and extracted withdichloromethane. Organic layer was dried and evaporated to give 1.4 g(100%) of methanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-6-ylmethylester.

2.5(+)-(6R)-9-(6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

A suspension of 0.514 g (2 mmol) of7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-onein 10 ml of anhydrous dimethylformamide was treated with 96 mg (2 mmol)of sodium hydride (50% suspension in mineral oil) and the resultingmixture was stirred for 40 min. 0.455 g (2 mmol) of methanesulfonic acid6,7-dihydro-5H-[1]pyrindin-6-ylmethyl ester in 2 ml of anhydrousdimethylformamide was added and the reaction mixture stirred at roomtemperature for 18 h. The solution was treated with water and extractedwith ethyl acetate. The organic phase was dried and evaporated to givecrude product, which was purified by silica gel chromatography, elutingwith ethyl acetate/methanol/diethyl amine in the proportions 98/2/0.2 togive 0.338 g of pure product obtained in the form of free base. Mp:156-185° C. [α]_(D) ²⁰=+13.6° (c=0.5, CH₂Cl₂).

Example 3 (Compound N^(o) 10 of Table 1B)(−)-(6S)-9-(6,7-Dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

By analogy with the method described in example 2, but replacing(−)-10,2-camphorsultam by the (+)-10,2-camphorsultam (Fluka), thecompound was obtained as a free base. Mp.: 156-185° C. [α]_(D) ²⁰=−14.1°(c=0.5, CH₂Cl₂).

Example 4 (Compound N^(o) 3 of Table 1B)(+/−)9-(2-Chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one4.1 (+/−) (2-Chloro-6,7-dihydro-5H-[1]pyrindin-6-yl)-methanol

To a solution of 1.83 g (9.26 mmol) of(+/−)2-chloro-6,7-dihydro-5H-[1]pyrindine-6 carboxylic acid (prepared byanalogy to the method described in WO99/02517) in 50 ml of anhydroustetrahydrofuran under argon was added 0.52 g (13.89 mmol) of lithiumaluminum hydride. The resulting mixture was stirred at room temperaturefor 2 h. Excess of lithium aluminum hydride was hydrolyzed with 2.13 mlof water and 0.53 ml of sodium hydroxide (15%). The precipitate wasfiltered off and washed with diethyl ether, the filtrate was evaporatedto give 1.61 g (95%) of product as an oil.

4.2 (+/−)Methanesulfonic acid2-chloro-6,7-dihydro-5H-[1]pyrindin-6-yl-methyl ester

The product was obtained by analogy with the method described in step2.4 and using (+/−) (2-chloro-6,7-dihydro-5H-[1]pyrindin-6-yl)-methanol.The product was used as such in the next step.

4.3(+/−)9-(2-Chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

The product was obtained by analogy with the method described in stepN^(o) 2.5 using (+/−)methanesulfonic acid2-chloro-6,7-dihydro-5H-[1]pyrindin-6-yl-methyl ester in place ofmethanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-6-ylmethyl ester. Thecompound was obtained in the form of free base. Mp: 186-187° C.

Example 5 (Compound N^(o) 2 of Table 1B)(+/−)7,7-Dimethyl-2-(pyrimidin-4-yl)-9-(2-phenyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidine-4-one

A solution of 0.22 g (0.52 mmol) of(+/−)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onein 3 ml of anhydrous toluene and 0.5 ml of ethanol was treated with0.625 ml (2M solution in water) of sodium carbonate, 36 mg (0.03 mmol)of tetrakis(triphenylphosphine)palladium and 0.095 g (0.780 mmol) ofphenyl-boronic acid. After being stirred for 24 h at 140° C., water wasadded, the mixture was extracted with dichloromethane. The organic phasewas dried and evaporated to give crude product, which was purified bysilica gel chromatography, eluting with dichloromethane/methanol/ammoniain the proportions 99/1/0.1 to give 0.133 g of pure product obtained inthe form of free base. Mp: 209-211° C.

Example 6 (Compound N^(o) 4 of Table 1B)(+/−)-9-(Chroman-3-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one6.1 (+/−) Methane sulfonic acid chroman-3-ylmethyl ester

The product was obtained by analogy with step N^(o) 1.3 and using (+/−)chroman-3-yl-methanol (U.S. Pat. No. 4,957,928, Eur. J. Med. Chem.,1987, 22(6), 539-544). The compound was used as such in the next step.

6.2(+/−)-9-Chroman-3-ylmethyl-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

By analogy with the method described in step N^(o) 1.4, using (+/−)methane sulfonic acid chroman-3-ylmethyl ester, the compound wasobtained in the form of free base. Mp: 84-86° C.

Example 7 (Compound N^(o) 5 of Table 1B)(+/−)-9-(6,7-Dihydro-5H-[2]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one7.1 (+/−)-(6,7-Dihydro-5H-[2]pyrindin-6-yl)-methanol

The product was obtained by analogy with step N^(o) 1.2 and using(+/−)-6,7-Dihydro-5H-[2]pyrindine-6-carboxylic acid ethyl ester(prepared by analogy to the method described in WO99/02517) and was usedas such in the next step.

7.2 (+/−)-Methanesulfonic acid 6,7-dihydro-5H-[2]pyrindin-6-ylmethylester

The product was obtained by analogy with step N^(o) 1.3 using(+/−)-(6,7-dihydro-5H-[2]pyrindin-6-yl)-methanol from step N^(o) è. 1.The compound was used as such in the next step.

7.3(+/−)-9-(6,7-Dihydro-5H-[2]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

By analogy with the method described in step N^(o) 1.4, using(+/−)-methanesulfonic acid 6,7-dihydro-5H-[2]pyrindin-6-ylmethyl ester,the compound was obtained in the form of free base. Mp: 169-171° C.

Example 8 (Compound N^(o) 6 of Table 1B)(−)-(S)-9(2,3-Dihydro-benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-oneoxalate (1:1) 8.1 (−)-(S)-(2,3-Dihydro-benzofuran-2-yl)methanol

The product was obtained by analogy with step N^(o) 1.2 and using(−)-(S)-2,3-dihydro-benzofuran-2-carboxylic acid (prepared by analogy tothe method described in J. Med. Chem., 1983, 26(3), 328-334) and wasused as such in the next step.

8.2 Methanesulfonic acid 2,3-dihydro-benzofuran-2-ylmethyl ester

The product was obtained by analogy with step N^(o) 1.3, using(−)-(S)-(2,3-dihydro-benzofuran-2-yl)methanol from step N^(o) 8.1, andwas used as such in the next step.

8.3(−)-(S)-9(2,3-Dihydro-benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-oneoxalate (1:1)

By analogy with the method described in step N^(o) 1.4, usingmethanesulfonic acid 2,3-dihydro-benzofuran-2-ylmethyl ester, thecompound was obtained in the form of free base which was transformedinto the oxalate salt. Mp: 168-170° C. [α]_(D) ²⁰=−1.40 (c=0.5, CH₃OH).

Example 9 (Compound N^(o) 7 of Table 1B)(+/−)9-(5-Fluoro-8-methoxy-chroman-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one9.1 (+/−)(5-Fluoro-8-methoxy-3,4,4a,8a-tetrahydro-2H-chromen-2-yl)-methanol

The product was obtained by analogy with step N^(o) 1.2 and using(+/−)5-fluoro-8-methoxy-3,4,4a,8a-tetrahydro-2H-chromene-2-carboxylicacid ester (prepared by analogy to the method described in U.S. Pat. No.5,137,901). The product was used as such in the next step.

9.2 (+/−)Methanesulfonic acid5-fluoro-8-methoxy-3,4,4a,8a-tetrahydro-2H-chromen-2-ylmethyl ester

The product was obtained by analogy with step N^(o) 1.3 and using (+/−)(5-fluoro-8-methoxy-3,4,4a,8a-tetrahydro-2H-chromen-2-yl)-methanol fromstep N^(o) 9.1. The product was used as such in the next step.

9.3(+/−)9-(5-Fluoro-8-methoxy-chroman-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

By analogy with the method described in step N^(o) 1.4, using (+/−)methanesulfonic acid5-fluoro-8-methoxy-3,4,4a,8a-tetrahydro-2H-chromen-2-ylmethyl ester, thecompound was obtained in the form of free base. Mp: 136-138° C.

Example 10 (Compound N^(o) 8 of Table 1B)(+/−)9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one10.1 (+/−)Methanesulfonic acid 2,3-dihydro-benzo[1,4]dioxin-2-ylmethylester

The product was obtained by analogy with step N^(o) 1.3 and using(+/−)-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol from Aldrich. Theproduct was used as such in the next step.

10.2(+/−)-9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

By analogy with the method described in step N^(o) 1.4, using (+/−)methanesulfonic acid 2,3-dihydro-benzodioxan-2-ylmethyl ester, thecompound was obtained in the form of free base. Mp: 105-107° C.

Example 11 (Compound N^(o) 12 of Table 1B)9-(2-Furo[2,3-b]pyridin-3-yl-ethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-onehydrochloride (1:1) 11.1 Furo[2,3-b]pyridin-3-yl-acetic acid ethyl ester

To a suspension of 0.325 g (8.14 mmol) of sodium hydride (50% suspensionin mineral oil) in 8 ml of anhydrous tetrahydrofuran was added 0.1 ml of1,1,1,3,3,3-hexamethyldisilazane and 1.81 g (8.14 mmol) of triethylphosphonoacetate (Aldrich) in 4 ml of anhydrous tetrahydrofuran. Theresulting mixture was stirred at room temperature for 1 h, cooled at 0°C. and there was added 1 g (7.4 mmol) of furo[2,3-b]pyridin-3-one(prepared according to J. Het. Chem. 1986, 23, 1465-1469). After beingstirred at room temperature for 24 h, water was added, the mixture wasextracted with dichloromethane. The organic phase was dried andevaporated to give crude product, which was purified by silica gelchromatography, eluting with ethyl acetate/cyclohexane in theproportions 40/60 to give 0.73 g of pure product.

11.2 2-Furo[2,3-b]pyridin-3-yl-ethanol

The product was obtained by analogy with step N^(o) 1.2 and usingfuro[2,3-b]pyridin-3-yl-acetic acid ethyl ester from step N^(o) 11.1.The product was used as such in the next step.

11.3 Methanesulfonic acid 2-furo[2,3-b]pyridin-3-yl-ethyl ester

The product was obtained by analogy with step N^(o) 1.3 and using2-furo[2,3-b]pyridin-3-yl-ethanol from step N^(o) 11.2. The product wasused as such in the next step.

11.49-(2-Furo[2,3-b]pyridin-3-yl-ethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one hydrochloride (1:1)

By analogy with the method described in step N^(o) 1.4, usingmethanesulfonic acid 2-furo[2,3-b]pyridin-3-yl-ethyl ester, the compoundwas obtained in the form of free base which was transformed into thehydrochloride salt. Mp: 181-183° C.

Example 12 (Compound N^(o) 14 of Table 1B)(+/−)-7,7-Dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6ylmethyl)-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one

By analogy with the method described in example 1, using (+/−)(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-yl)-methanol in place of (+/−)(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-yl)-methanol, the compound wasobtained as a free base. Mp.: 163-164° C.

A list of chemical structures and physical data for compounds of theaforementioned formula (I), wherein R1 is a pyrimidine ring,illustrating the present invention is given in tables 1B and 2B. Thecompounds have been prepared according to the methods of the examples.

In the tables

(rac.) means racemic mixture,

(−) means levo isomer,

(+) means dextro isomer,

(R) means absolute R configuration and

(S) means absolute S configuration.

In the tables 1B and 2B, R1 is an unsubstituted 4-pyrimidine ring; inthe column “X”, when X represents two hydrogen atoms, only “H” isindicated; “m” and “p” equal 1.

TABLE 1B (I)

N° X Y R2 R3 R4 R5 n Mp ° C. Salt 1 H bond

CH₃ CH₃ H 0 193-195 Hydrochloride (1:1) 2 H bond

CH₃ CH₃ H 0 209-211 Free base 3 H bond

CH₃ CH₃ H 0 186-187 Free base 4 H bond

CH₃ CH₃ H 0 84-86 Free base 5 H bond

CH₃ CH₃ H 0 169-171 Free base 6 H bond

CH₃ CH₃ H 0 168-170 Oxalate (1:1) 7 H bond

CH₃ CH₃ H 0 136-138 Free base 8 H bond

CH₃ CH₃ H 0 105-107 Free base 9 H bond

CH₃ CH₃ H 0 162-164 Free base 10 H bond

CH₃ CH₃ H 0 156-185 Free base 11 H bond

CH₃ CH₃ H 0 156-185 Free base 12 H bond

CH₃ CH₃ H 1 181-183 Hydrochloride (1:1) 13 H bond

CH₃ CH₃ H 0 155-156 Free base 14 H bond

CH₃ CH₃ H 0 163-164 Free base

TABLE 2B (I)

N° X Y R2 R3 R4 R5 n Mp ° C. salt 1 H bond

H CH₃ (Rac.) H 0 173-175 (1:1) Hydrochloride 2 H bond

CH₃ CH₃ H 0 181-183 Free base 3 H bond

H CH₃ (Rac.) H 0 117-119 (1:1) Hydrochloride 4 H bond

H CH₃ (Rac.) H 0 211-213 Free base 5 H bond

CH₃ CH₃ H 0 191-193 Free base 6 H bond

CH₃ CH₃ H 0 161-163 Free base 7 H bond

CH₃ CH₃ H 0 228-230 Free base 8 H bond

H CH₃ (Rac.) H 0 159-161 Free base 9 H bond

H CH₃ (Rac.) H 0 188-190 Free base 10 H bond

CH₃ CH₃ H 0 196-198 Free base 11 H Bond

H CH₃ (Rac.) H 0 130-132 Free base 12 H Bond

CH₃ CH₃ H 0 160-162 Free base 13 H Bond

CH₃ CH₃ H 0 156-158 Free base 14 H Bond

H CH₃ (Rac.) H 0 177-179 Free base 15 H Bond

H CH₃ (Rac.) H 0 125-127 Free base 16 H Bond

H CH₃ (Rac.) H 0 161-163 Free base

Test Example Inhibitory Activity of the Medicament of the PresentInvention Against GSK3β

Two different protocols can be used.

In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mMTris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3β (totalreaction volume: 100 microliters).

In a second protocol: 4.1 μM of prephosphorylated GS1 peptide and 42 μMATP (containing 260,000 cpm 33P-ATP) were incubated in 80 mM Mes-NaOH,pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02%Tween 20, 10% glycerol buffer for 2 hours at room temperature in thepresence of GSK3β.

Inhibitors were solubilized in DMSO (final solvent concentration in thereaction medium, 1%).

The reaction was stopped with 100 microliters of a solution made of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml and thendiluted to 1:100 before use. An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated 33P radioactivity was determinedby liquid scintillation spectrometry.

The phosphorylated GS-1 peptide had the following sequenceNH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH.

The GSK3β inhibitory activity of the compounds of the present inventionare expressed in IC₅₀, and as an illustration the range of IC₅₀'s of thecompounds:

in table 1A is between 5 nanomolar to 2 micromolar concentrations;

in table 2A is between 70 nanomolar to 2 micromolar concentrations

in table 1B is between 5 nanomolar to 2 micromolar concentrations;

in table 2B is between 15 nanomolar to 2 micromolar concentrations.

Test Example 2 Inhibitory Activity of the Medicament of the PresentInvention Against cdk5/p25

The following protocol may be used

0.4 mg/ml Histone H1 and 10 μM ATP (containing 300,000 cpm of ³³P-ATP)were incubated in 50 mM Hepes, pH 7.2, 1 mM DTT, 1 mM MgCl₂, 1 mM EGTA,0.02% Tween 20 buffer for 1 hour at room temperature in the presence ofcdk5/p25 (total reaction volume: 100 microliters).

Inhibitors were solubilized in DMSO (final solvent concentration in thereaction medium, 1%).

The reaction was stopped with 100 microliters of a solution of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml (dilutedto 1:100 before use). An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated ³³P radioactivity was determinedby liquid scintillation spectrometry.

The cdk5/p25 inhibitory activity of the compounds of the presentinvention are expressed as IC₅₀ values. Typically, 3-fold serialdilutions of the inhibitor over at least a 1000-fold concentration rangeare used.

As an illustration the range of IC₅₀'s of the compounds:

in table 1A is between 50 nanomolar to 2 micromolar concentrations;

in table 2A is >1 micromolar concentrations;

in table 1B is between 200 nanomolar to 5 micromolar

in table 2B is >1 micromolar concentrations.

Formulation Example

(1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus.

Compound of Example 1  30 mg Crystalline cellulose  60 mg Corn starch100 mg Lactose 200 mg Magnesium stearate  4 mg(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules.

Compound of Example 1 30 mg Olive oil 300 mg  Lecithin 20 mg(1) Parenteral Preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule.

Compound of Example 1 3 mg Sodium chloride 4 mg Distilled water forinjection 1 ml

INDUSTRIAL APPLICABILITY

The compounds of the present invention have GSK3β or GSK3β and cdk5/p25inhibitory activity and are useful as an active ingredient of amedicament for preventive and/or therapeutic treatment of diseasescaused by abnormal activity of GSK3β or GSK3β and cdk5/p25 and moreparticularly of neurodegenerative diseases.

1. A method of inhibiting the activity of glycogen synthase kinase3-beta (GSK3-β), which comprises administering to a patient in need ofsaid inhibition a therapeuticcally effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof:

wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atomor a C₁₋₂ alkyl group and a hydrogen atom; Y represents a bond, anethenylene group, an ethynylene group or a methylene group optionallysubstituted by one or two groups chosen from a C₁₋₆ alkyl group, ahydroxy group or a C₁₋₄ a hydroxy group; R1 represents a 2, 3 or4-pyridine ring or a 2, 4 or 5-pyrimidine ring, the ring beingoptionally substituted by a C₃₋₆ cycloalkyl group, a C₁₋₄ alkyl group, aC₁₋₄ alkoxy group, a benzyl group or a halogen atom; R2 represents aheterocyclic ring having 1-4 heteroatoms selected from an oxygen atom, asulfur atom and a nitrogen atom and having 5-9 carbon atoms, of formula

wherein A, B, C and D represent, each independently, a carbon atom or anitrogen atom and W represent a saturated or unsaturated 5, 6 or 7membered cyclic ring having from 3 to 7 carbon atoms and 2 to 0heteroatoms selected from an oxygen atom, a sulfur atom or a nitrogenatom; the R2 group being optionally substituted on a carbon atom or,when possible, on a nitrogen atom by one or two atoms or groups chosenfrom a halogen atom, a C₁₋₆ alkyl group, a hydroxy group, a C₁₋₄ alkoxygroup, a benzene ring, a pyridine ring or a —NR6R7 group; R3 representsa hydrogen atom, a C₁₋₆ alkyl group, a hydroxy group, a C₁₋₄ alkoxygroup or a halogen atom; R4 represents a hydrogen atom, a C₁₋₆ alkylgroup, a C₁₋₄ alkoxy group or a halogen atom; R5 represents a hydrogenatom, a C₁₋₆ alkyl group, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃halogenated alkyl group or a halogen atom; R6 and R7 represent, eachindependently, a hydrogen atom, a C₁₋₆ alkyl group, a benzyl group, abenzene ring or R6 and R7 represent together with the nitrogen atom, apyrrolidine ring, a piperidine ring, a hexamethyleneimine ring, amorpholine ring or a piperazine ring, the ring being optionallysubstituted by one or two C₁₋₆ alkyl group; when m equals 0, p equals 1,2 or 3, when m equals 1, p equals 0, 1 or 2, when m equals 2, p equals 0or 1; when m equals 3, p equals 0; and n represents 0 to 3; with theproviso that the compound of formula (I) is not:9-[2-(1H-indol-3-yl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-α]pyrimidin-4-one;9-[3-(1H-indol-3-yl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-α]pyrimidin-4-one;1-[2-(1H-Indol-3-yl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-α]pyrimidin-5(1H)-one, or1-[3-(1H-indol-3-yl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-α]pyrimidin-5(1H)-one.
 2. The method according to claim 1, wherein R1 represents anunsubstituted pyridinyl group or an unsubstituted 4-pyrimidine ring. 3.The method according to claim 1, wherein the compound is selected fromthe group consisting of:(+)-(6R)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(−)-(6S)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(+)-(6R)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(±)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(+)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(−)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]-pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(±)-9-(2,3-dihydro-benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;9-(furo[3,2-b]pyridin-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;9-(benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(±)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(±)7,7-dimethyl-2-(pyridin-4-yl)-9-[2-(pyridin-4-yl)-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl]-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one;(±)7,7-dimethyl-9-(2-phenyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one;(±)7,7-dimethyl-2-(pyridin-4-yl)-9-[2-(pyrrolidin-1-yl)-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl]-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(±)7,7-difluoro-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one;and9-((+)-(6-R)-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-(±)-7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one;or a pharmaC hd 1 eutiC hd 1 ally aC hd 1 C hd 1 eptable salt thereof.4. The method according to claim 1, wherein the compound is selectedfrom the group consisting of:9-chroman-2-ylmethyl-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-chroman-2-ylmethyl-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-furo[3,2-b]pyridin-2-ylmethyl-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[2]pyrindin-6-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one or a pharmaceuticallyacceptable salt thereof.
 5. The method according to claim 1, wherein thecompound is selected from the group consisting of:9-(6,7-dihydro-5H-cyclopentapyrazin-6-ylmethyl)-7,7-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)7,7-dimethyl-2-(pyrimidin-4-yl)-9-(2-phenyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one(±)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)-9-(chroman-3-y1methyl)-7,7-dimethy1-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)-9-(6,7-dihydro-5H-[2]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(−)-(S)-9-(2,3-dihydro-benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)-9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(−)-(6S)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(+)-(6R)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(2-furo[2,3-b]pyridin-3-yl-ethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-benzofuran-2-ylmethyl-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6ylmethyl)-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-oneor a pharmaC hd 1 eutiC hd 1 ally aC hd 1 C hd 1 eptable salt thereof.6. The method according to claim 1, wherein the compound is selectedfrom the group consisting of:9-(8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-chroman-2-ylmethyl-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-chroman-2-ylmethyl-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one 9-(8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(5-methoxy-2,3-diliydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-furo[3,2-b]pyridin-2-ylmethyl-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyriniido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one or9-(6,7-dihydro-5H-[2]pyrindin-6-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one or a pharmaceuticallyacceptable salt thereof.
 7. A method of inhibiting the activity ofcdk5/p25 enzyme, which comprises administering to a patient in need ofsaid inhibition an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof:

wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atomor a C₁₋₂ alkyl group and a hydrogen atom; Y represents a bond, anethenylene group, an ethynylene group or a methylene group optionallysubstituted by one or two groups chosen from a C₁₋₆ alkyl group, ahydroxy group or a C₁₋₄ alkoxy group; R1 represents a 2,3 or 4-pyridinering or a 2,4 or 5-pyrimidine ring, the ring being optionallysubstituted by a C₃₋₆ cycloalkyl group, a C₁₋₄ alkyl group, a C₁₋₄alkoxy group, a benzyl group or a halogen atom; R₂ represents aheterocyclic bicyclic ring having 1-4 heteroatoms selected from anoxygen atom, a sulfur atom and a nitrogen atom and having 5-9 carbonatoms, of formula

wherein A, B, C and D represent, each independently, a carbon atom or anitrogen atom and W represent a saturated or unsaturated 5,6 or 7membered cyclic ring having from 3 to 7 carbon atoms and 2 to 0heteroatoms selected from an oxygen atom, a sulfur atom or a nitrogenatom; the R2 group being optionally substituted on a carbon atom or,when possible, on a nitrogen atom by one or two atoms or groups chosenfrom a halogen atom, a C₁₋₆ alkyl group, a hydroxy group, a C₁₋₄ alkoxygroup, a benzene ring, a pyridine ring or a —NR6R7 group; R3 representsa hydrogen atom, a C₁₋₆ alkyl group, a hydroxy group, a C₁₋₄ alkoxygroup or a halogen atom; R4 represents a hydrogen atom, a C₁₋₆ alkylgroup, a C₁₋₄ alkoxy group or a halogen atom; R5 represents a hydrogenatom, a C₁₋₆ alkyl group, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃halogenated alkyl group or a halogen atom; R6 and R7 represent, eachindependently, a hydrogen atom, a C₁₋₆ alkyl group, a benzyl group, abeuzene ring or R6 and R7 represent together with the nitrogen atom, apyrrolidine ring, a piperidine ring, a hexamethyleneimine ring, amorpholine ring or a piperazine ring, the ring being optionallysubstituted by one or two C₁₋₆ alkyl group; when m equals 0, p equals 1,2 or 3, when m equals 1, p equals 0, 1 or 2, when m equals 2, p equals 0or 1; when m equals 3, p equals 0; and n represents 0 to 3; with theproviso that the compound of formula (I)is not:9-[2-(1H-indol-3-yl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-α]pyrimidin-4-one;9-[3-(1H-indol-3-yl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-α]pyrimidin-4-one;1-[2-(1H-Indol-3-yl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-α]pyrimidin-5(1H)-one, or1-[3-(1H-indol-3-yl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-α]pyrimidin-5(1H)-one.
 8. The method according to claim 7, wherein R1 represents anunsubstituted pyridinyl group or an unsubstituted 4-pyrimidine ring. 9.The method according to claim 7, wherein the compound is selected fromthe group consisting of:(+)-(6R)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(−)-(6S)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(+)-(6R)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(±)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(+)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(−)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]-pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(±)-9-(2,3-dihydro-benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;9-(furo[3,2-b]pyridin-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;9-(benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(±)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(±)7,7-dimethyl-2-(pyridin-4-yl)-9-[2-(pyridin-4-yl)-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl]-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one;(±)7,7-dimethyl-9-(2-phenyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one;(±)7,7-dimethyl-2-(pyridin-4-yl)-9-[2-(pyrrolidin-1-yl)-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl]-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;(±)7,7-difluoro-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one;and9-((+)-(6-R)-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-(±)-7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one; or a pharmaC hd 1 eutiC hd 1 ally aC hd 1 C hd1 eptable salt thereof.
 10. The method according to claim 7, wherein thecompound is selected from the group consisting of:9-chroman-2-ylmethyl-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-chroman-2-ylmethyl-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-furo[3,2-b]pyridin-2-ylmethyl-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[2]pyrindin-6-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one or a pharmaceuticallyacceptable salt thereof.
 11. The method according to claim 7, whereinthe compound is selected from the group consisting of:9-(6,7-dihydro-5H-cyclopentapyrazin-6-ylmethyl)-7,7-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)7,7-dimethyl-2-(pyrimidin-4-yl)-9-(2-phenyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-6,7,8,9-tetrahydro-pyrimido[1,2-]pyrimidine-4-one(±)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)-9-(chroman-3-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)-9-(6,7-dihydro-5H-[2]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(−)-(S)-9-(2,3-dihydro-benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)-9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(−)-(6S)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(+)-(6R)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(2-furo[2,3-b]pyridin-3-yl-ethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one 9-benzofuran-2-ylmethyl-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one(±)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6ylmethyl)-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-oneor a pharmaceutically acceptable salt thereof.
 12. The method accordingto claim 7, wherein the compound is selected from the group consistingof:9-(8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-chroman-2-ylmethyl-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-chroman-2-ylmethyl-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido [1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-furo[3,2-b]pyridin-2-ylmethyl-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one9-(6,7-dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one or9-(6,7-dihydro-5H-[2]pyrindin-6-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one or a pharmaceuticallyacceptable salt thereof.